With progress in the micromachining technique, a micronanopore-using analysis technique of a biopolymer such as a virus, protein, and DNA in a liquid phase has been developed.
There are two main micronanopore analysis techniques, as follows.
1) Detection Technique
Detecting a physical change (a change in current, for example) at the time when a target particle such as a virus, protein, and DNA passes through the pore; and
2) Transfer Control Technique
Passing target particles such as a virus, protein, and DNA through in the pore having micrometer size or nanometer size by drawing the particles to the proximity of the pore.
A typical detection technique is performed as follows. A tank of a lid-opened structure is prepared and the tank is divided into a right chamber and a left chamber by an insulating plate. A pore is pierced through the insulating plate. The left chamber is filled with a first electrolytic solution and the right chamber is filled with a second electrolytic solution. For example, target particles are dispersed in the first electrolytic solution. First and second metal electrodes made of the same material are immersed in the first and second electrolytic solutions, respectively. The first and second metal electrodes are connected to a power source.
A measuring method of target particles using such a detection device will now be explained.
A desired voltage from the power source is applied between the first and second metal electrodes to supply a current through the first electrolytic solution, pore, and second electrolytic solution in this order. In this state, the target particles dispersed in the first electrolytic solution in the left chamber are transferred into the pore. When a particle enters the pore, resistivity between the first and second metal electrodes also changes based on the size of the particle. As a result, a value of the current through the first electrolytic solution, pore, and second electrolytic solution in this order changes. The size of the target particle can be detected by observing a time response-current change relationship.
Particles dispersed in the liquid phase are negatively charged (have a zeta potential) in general, and thus, a transfer control technique is adopted in many cases. The transfer control technique uses the voltage used in the detection technique to pass the target particles through the pore. That is, when a voltage is applied from the power source to the first and second electrodes, the potential of the first electrolytic solution with target particles dispersed therein is set to be negative and the potential of the second electrolytic solution is set to be positive. In this state, a repulsive force works on the negatively-charged target particles in the first electrolytic solution of negative potential, and the particles are electrically transferred to the second electrolytic solution through the pore.
Note that, if the power source of direct current is used, the flow of the current goes opposite to the transfer direction of the target particles.
If a high voltage is applied between the first and second electrolytic solutions to secure both the detection technique and the transfer control technique, the electrolytic solutions may be altered by electrolysis and the measurement may become unstable. Therefore, the applied voltage should be made as small as possible, specifically, approximately 1 to 2V. When the voltage of approximately 1 to 2V is applied, the current value changes depending on the property of the electrolytic solution and a physical size of the pore. Generally, a suitable current value during the voltage application should be set to an order of a nanoampere or a picoampere.
In other words, a device configured to measure a particle such as virus, protein, and DNA in a liquid phase using a pore is required to measure a current value of an order of a nanoampere or a picoampere at a response speed of approximately 100 to 500 KHz.
In such a device, a sensor including a pore and the like and a current measurement unit which measures the current running through the pore must be connected with the shortest distance to measure the current value of an order of a nanoampere or a picoampere at the response speed of approximately 100 to 500 KHz with a high signal-to-noise ratio.
However, conventionally, a power source must be connected in series to both the sensor including the pore and the like and the current measurement unit. If the power source is connected in series to the sensor and the current measurement unit, a length of the interconnection therebetween increases, and a stray capacitance of the interconnection itself increases. Furthermore, the power source itself may increase the stray capacitance. The increased stray capacitance causes a low response speed of a measured current value (because the capacitance components degrade the waveform sharpness) and a low signal-to-noise ratio of a measured current value.
Furthermore, if a commercial power source is used as the power source, the detection signal itself becomes minute, specifically, a microampere or a nanoampere. Therefore, alternating-current components of the commercial power source must be kept under a microampere or a nanoampere, or the alternating-current components overlapping the measurement result cause a great error. A complex power circuit structure is required to remove such alternating-current components of the commercial power source from the current value of an order of nanoampere or a picoampere, and such a complex power circuit structure will increase the stray capacitance and lower the response speed, and furthermore, manufacturing costs of the device will become high by such a complex structure.